Bosentan is a dual endothelin receptor antagonist important in the treatment of pulmonary artery hypertension (PAH). The chemical name of Bosentan is p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-Methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide and it is structurally represented by formula-(I). Bosentan Monohydrate is pharmaceutically active substance and marketed under the brand name TRACLEER® as immediate release tablets. Bosentan is a competitive antagonist of endothelin-1 at the endothelin-A (ET-A) and endothelin-B (ET-B) receptors. Under normal conditions, endothelin-1 binding of ET-A or ET-B receptors causes pulmonary vasoconstriction. By blocking this interaction, Bosentan decreases pulmonary vascular resistance. Bosentan has a slightly higher affinity for ET-A than ET-B.
U.S. Pat. No. 5,292,740 (hereinafter referred to as the '740 patent) discloses various sulfonamide derivatives, processes for their preparation, pharmaceutical compositions and methods of use thereof. Among them, Bosentan, p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinylbenzenesulfonamide Monohydrate, has a wide variety of biological activities including inhibiting the renin angiotensin system and acting as an endothelin antagonist. The process as disclosed in '740 is illustrated as Path A in Scheme-1. 5-(2-methoxyphenoxy)-2-(2-pyrimidin-2-yl)-4,6(1H,5H)-pyrimidinedione is reacted with phosphorous oxychloride in acetonitrile to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine, which is further condensed with 4-tert-butylbenzenesulfonamide potassium in dimethylsulfoxide followed by treatment with hydrochloric acid to obtain p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide. The p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamide is then reacted with a sodium ethylene glycol, prepared by the reaction of ethylene glycol and sodium metal in ethylene glycol solvent, to produce Bosentan as sodium salt. The product formed by this method requires three further crystallizations to provide specification grade Bosentan suitable for formulation.
The '740 patent describes the use of sodium metal for the preparation of sodium ethylene glycolate. Sodium metal is an explosive and hazardous reagent and vigorously reacts with water. The use of sodium metal is not advisable for scale up operations. Moreover, the Bosentan obtained by the process described in the '740 patent using sodium metal is not satisfactory from a purity and yield perspective. The overall yield of sulphonamide derivatives by the said process of '740 patent is 53%. Further, the process of '740 patent also leads to formation of unacceptable amounts of impurities along with Bosentan.
Another process for the preparation of Bosentan is reported in U.S. Pat. No. 6,136,971 (hereinafter referred to as the '971 patent) which is multi-step process as illustrated in Path B of Scheme-1. 5-(2-methoxyphenoxy)-2-(2-pyrimidin-2-yl)-4,6(1H,5H)-pyrimidinedione is reacted with phosphorous oxychloride in toluene to obtain 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine, which is further condensed with 4-tert-butylbenzenesulfonamide in the presence of anhydrous potassium carbonate and a phase transfer catalyst (e.g., benzyltriethylammonium chloride) in toluene to obtain p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide potassium salt. The p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide potassium salt is then reacted with ethylene glycol mono-tert-butyl ether in toluene in the presence of granular sodium hydroxide to produce p-tert-butyl-N-[6-(2-tert-butyl-ethoxy)-5-(2-methoxyphenoxy)-[2,2′-bipyrimidin]-4-yl]benzenesulfonamide (Bosentan tert-butyl ether). The Bosentan tert-butyl ether obtained is then reacted with formic acid followed by treatment with absolute ethanol to obtain Bosentan formate monoethanolate. The Bosentan formate monoethanolate is further treated with sodium hydroxide in absolute ethanol and water followed by acidic hydrolysis by treating with hydrochloric acid and then the resulting precipitate is suction-filtered; washed with ethanol-water mixture (1:1) to give crude Bosentan. The crude Bosentan obtained is then purified with mixture of ethanol and water and the resulting precipitate is suction-filtered to give pure Bosentan.

Subsequently few more processes reported in WO 2009/095933A2, WO 2009/112954 A2, WO 2009/093739A1 and WO 2010/032261A1 also follow the reaction sequence represented in Path A of Scheme-1 using multi step processes.
Thus the processes reported in the prior art has following disadvantages:                i) Use of sodium metal which is difficult and not advisable to handle for scale-up operations;        ii) Use of multi-step synthesis where in intermediate are isolated by means of either filtration or centrifugation and subsequent drying of the obtained intermediates before using the same in the next step. The isolation and drying is a very critical step in the production which exposes the production executives to different solvent vapours and also to the isolated solids while handling. The time required to produce a batch is substantially increased as the number of isolations are increased during the production scale and thus multi-step reactions involving multiple filtrations, drying are not suitable for the production;        iii) The processes described in the art does not have satisfactory purity and unacceptable amounts of impurities are generally formed along with product and        iv) Use of ethylene glycol as a solvent along with sodium metal causes formation of high concentration of dimer impurity of formula (VI) which is very difficult to remove from the Bosentan.        
                v) The prior art processes use strong base and high temperature which leads to generation of 6-hydroxy impurity of formula (VII) at higher concentration.        

Hence, there remains a need for providing efficient, industrially feasible and economically viable process for the manufacture of Bosentan to substantially eliminate the problems associated with the prior art, and that will be suitable for large-scale preparation such that the process will be safe to handle, simple and easy to carry out, high yield and purity of the product.